Thermal and microwave-assisted N-formylation using solid-supported reagents

Article abstract of DOI:10.1016/j.tetlet.2004.12.044

A rapid and easy route to formamides by microwave assisted N-formylation of primary and secondary amines is described. Using an insoluble polymer or an inorganic solid-supported reagent as a formylating agent, microwave irradiation furnished the corresponding formamides in high yields, with reduced reaction time and solvent volume over the conventional approach.

Full text of DOI:10.1016/j.tetlet.2004.12.044

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 955–957
Thermal and microwave-assisted N-formylation using
solid-supported reagents
Bimbisar Desai,a,* Timothy N. Danksa,b and Gabriele Wagnera
aChemistry Division, SBMS, University of Surrey, Guildford, Surrey GU2 7XH, UK
bThe Oratory School, Woodcote, Reading RG8 0PJ, UK
Received 23 November 2004; accepted 8 December 2004
Abstract—A rapid and easy route to formamides by microwave assisted N-formylation of primary and secondary amines is
described. Using an insoluble polymer or an inorganic solid-supported reagent as a formylating agent, microwave irradiation fur-
nished the corresponding formamides in high yields, with reduced reaction time and solvent volume over the conventional approach.
ꢀ 2004 Elsevier Ltd. All rights reserved.
In the past few years, chemistry under microwave
heating has been under intense study with significant
benefits in the area of organic synthesis.1 Reagents sup-
ported on organic polymers2 and/or on the surface of
inorganic matrices2 have been instrumental in the devel-
opment of automated parallel synthesis of chemical
libraries, particularly in connection with microwave
heating.3
cally important compounds and also in general organic
synthesis. The synthesis of formamides by the way of N-
formylation of amines using known and new formylat-
ing agents is documented.7,8 However, most of them in-
volve longer reaction times under classical reaction
conditions and generally a non-recoverable formylating
agent.
In continuation with our ongoing work, we investigated
the use of a polymer-supported formate in studying
microwave-induced catalytic transfer hydrogenation
(CTH) for benzyl deprotection. The polymer supported
formate utilised in this study was prepared using the
procedure described previously.4 The formate loading
was determined as 2.5 mmol/g resin by potentiometric
titration.
During our previous studies, we reported on microwave-
assisted transfer hydrogenation of electron-deficient
alkenes in high yield, using WilkinsonÕs catalyst in
connection with formate or formic acid supported either
on an ion-exchange resin4 or on alumina,5 as a recycla-
ble hydrogen source. A recent report6 extended the use
of polymer-supported formate to the reduction of
conjugated alkenes and an imine, under classical
heating.
Initially we attempted the N-debenzylation of N-benzyl-
p-anisidine 1 under microwave irradiation. A mixture of
the polymer-supported formate 2, 10 % Pd/C catalyst
and N-benzyl-p-anisidine 1 in a minimum quantity of
DMSO was microwave irradiated at 100 W for 30 s.
Upon filtration, extraction and removal of the solvent,
the isolated compound showed no evidence of the
desired N-debenzylation product 3. Interestingly
however, the isolated compound was characterised as
N-benzyl-N-formyl-p-anisidine 4 resulting from the
N-formylation of the starting amine (see Scheme 1). In
view of this result and due to the fact that, to our knowl-
edge, the use of inexpensive and recyclable polymer-sup-
ported formate as a formylating agent together with the
advantages of microwave flash heating was never
Herein we wish to report on the use of polymer (ion-ex-
change resin) and inorganic solid-supported reagents as
a formylating agent to produce formamides starting
from primary and secondary amines. Formamides are
important precursors in the synthesis of pharmaceuti-
Keywords: Formamides; Microwave irradiation; Solid-supported
formate.
*
Corresponding author at present address: Institute of Chemistry,
Organic and Bioorganic Chemistry, Heinrichstrasse 28, A-8010 Graz,
Austria. Tel.: +43 316 380 5336; fax: +43 316 380 9840; e-mail:
udayandesai@yahoo.com
0040-4039/$ - see front matter ꢀ 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.044

956
B. Desai et al. / Tetrahedron Letters 46 (2005) 955–957
In
a typical reaction, benzylamine 5a (0.049 g,
0.45 mmol) and solid-supported formate (1 g, corre-
sponding to 2–2.5 mmol formate) were suspended in
DMSO (0.5 mL) in a glass vial equipped with a screw
cap. The reaction mixture was irradiated with micro-
waves (MW-10 Microwell microwave reactor) at
100 W for 30 s. On cooling, the mixture was diluted with
dichloromethane (1 mL) and filtered under gravity. The
filtrate was extracted with brine (2 · 5 mL), dried and
evaporated under reduced pressure to give a colourless
solid identified as N-benzylformamide 6a (0.058 g,
95%) by comparison of its spectroscopic data (1H
NMR, 13C NMR, IR and MS) and melting point with
those of an authentic sample.9
Scheme 1.
To further investigate the scope of the reaction, other
primary and secondary amines were studied under sim-
ilar reaction conditions (see Table 1). All amines con-
reported in the literature, our studies were directed into
optimisation of the reaction conditions for N-formyla-
tion of primary and secondary amines.
Table 1. Thermal and microwave assisted formylation of primary and secondary amines using a polymer-supported formate
Entry
Amine
R
R0
Product
Yield (%)
MWa
Thermalb
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
Ph
PhCH2
H
6a
6b
6c
6d
6e
6f
90
95
95
80
95
60
60
60
80
85
60
80
55
50
H
PhCH3CH
p-CH3OC6H4
PhCH2
H
H
PhCH2
HN(CH2CH2)2
O(CH2CH2)2
5g
6g
a All microwave irradiations were performed at 100 W for 30 s.
b All thermal reactions were carried out at 70–80 ꢁC for 4h in DMSO.
Table 2. Thermal and microwave assisted formylation of primary and secondary amines using alumina supported formic acid
Entry
Amine
R
R0
Product
Yield (%)
MWa
Thermalb
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
Ph
PhCH2
H
6a
6b
6c
6d
6e
6f
93
95
85
80
95
60
60
70
85
80
55
80
55
50
H
PhCH3CH
p-CH3OC6H4
PhCH2
H
H
PhCH2
HN(CH2CH2)2
O(CH2CH2)2
5g
6g
a All microwave irradiations were performed at 100 W for 30 s.
b All thermal reactions were carried out at 70 ꢁC for 3–4h in DMSO.

B. Desai et al. / Tetrahedron Letters 46 (2005) 955–957
957
verted readily into the corresponding formamides.
Acknowledgements
Piperazine 5f was formylated at both secondary amine
groups simultaneously to give piperazine dicarbalde-
hyde 6f.
We thank the Personal Chemistry (now Biotage) for
financial support and provision of a MW-10 microwell
microwave reactor.
Formic acid supported on basic alumina, previously
reported as a transfer hydrogenation source,5 could also
be demonstrated to act as a formylating agent. Under
microwave and conventional heating, the alumina
supported formic acid 7, with a typical loading of
2 mmol/g, was now also applied to selected primary
and secondary amines yielding the corresponding
formamides (see Table 2). Overall, the polymer sup-
ported or alumina supported reagent both provided com-
parable results with respect to reaction rates and yields.
References and notes
1. (a) Microwave Assisted Organic Synthesis; Tierney, J.,
Lidstro¨m, P., Eds.; Blackwell: Oxford (UK), 2004; (b)
Loupy, A. Microwaves in Organic Synthesis; Wiley-VCH:
Weinheim, 2002; (c) Hayes, B. L. Microwaves: Chemistry at
the Speed of Light; CEM Publishing: Matthews NC, 2002;
(d) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225.
2. (a) Kirschning, A.; Monenschein, H.; Wittenberg, R.
Angew. Chem., Int. Ed. 2001, 40, 650; (b) Ley, S. V.;
Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A.
G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Store, R. I.;
Taylor, S. J. J. Chem. Soc., Perkin Trans. 1 2000,
3815.
3. (a) Desai, B.; Kappe, C. O. Microwave-Assisted Synthesis
Involving Immobilized Catalysts. Top. Curr. Chem. 2004,
242, 177; (b) Ley, S. V.; Baxendale, I. R. Nat. Rev. Drug
Discov. 2002, 1, 573; (c) Kappe, C. O. Curr. Opin. Chem.
Biol. 2002, 6, 314; (d) Mavandadi, F.; Lidstro¨m, P. Curr.
Top. Med. Chem. 2004, 4, 773.
4. Desai, B.; Danks, T. N. Tetrahedron Lett. 2001, 42,
5963.
5. Danks, T. N.; Desai, B. Green Chem. 2002, 4, 179.
6. Basu, B.; Bhuiyan, Md. M. H.; Das, P.; Hossain, I.
Tetrahedron Lett. 2003, 44, 8931.
In all cases, it was noted that reactions conducted using
microwave irradiation showed an improvement in yields
in the range of 5–30% over the classical heating
approach. Also, the reaction protocols under microwave
heating utilise reduced solvent volume (0.5 mL). In
general, using either of the formylating reagents, nota-
ble yield improvements for anilines (Tables 1 and 2,
entries 1 and 4) were observed. Primary or secondary
benzylamines (Tables 1 and 2, entries 2, 3 and 5) showed
good to excellent yields within 30 s of microwave irradi-
ation. However, the heterocyclic secondary amines
(Tables 1 and 2, entries 6 and 7) maintained moderate
yields with negligible difference under either heating
conditions.
In summary, we have demonstrated that formate or for-
mic acid immobilised on a solid support (polymer ma-
trix or inorganic solid) can not only function as a
transfer hydrogenation source but also as a formylating
agent. The latter application allows for simplified syn-
thesis of industrially important formamides with ease
of purification and isolation, and in high to excellent
yields. The use of recyclable solid supported reagents
combined with microwave irradiation renders the reac-
tion suitable for automated combinatorial and parallel
synthesis protocols, or other contemporary synthetic
chemistry techniques.
7. (a) Jung, S. H.; Ahn, J. H.; Park, S. Y.; Choi, J.-K. Bull.
Korean Chem. Soc. 2002, 23, 149; (b) Okano, T.; Harada,
N.; Kiji, J. Bull. Chem. Soc. Jpn. 1994, 67, 2329; (c) Reddy,
G. P.; Baskaran, S. Tetrahedron Lett. 2002, 43, 1919; (d) Li,
H.-Z.; Li, H.-Y.; Xiao, L.-W.; Wang, K.-F. Youji Huaxane
2003, 23, 883.
8. (a) Hill, D. R.; Hsiao, C. N.; Kurukulasuriya, R.; Witten-
berg, S. J. Org. Lett. 2002, 4, 111; (b) Chakrabarty, M.;
Khasnobis, S.; Harigaya, Y.; Konda, Y. Synth. Commun.
2000, 30, 187; (c) Katritzky, A. R.; Chang, H.-X.; Yang, B.
Synthesis 1995, 5, 503.
9. Sekiya, M.; Tommie, M.; Leonard, N. J. J. Org. Chem.
1968, 33, 318.